Predicting CPAP failure after less invasive surfactant administration (LISA) in preterm infants by machine learning model on vital parameter data: a pilot study.

Objective. Less invasive surfactant administration (LISA) has been introduced to preterm infants with respiratory distress syndrome on continuous positive airway pressure (CPAP) support in order to avoid intubation and mechanical ventilation. However, after this LISA procedure, a significant part of infants fails CPAP treatment (CPAP-F) and requires intubation in the first 72 h of life, which is associated with worse complication free survival chances. The aim of this study was to predict CPAP-F after LISA, based on machine learning (ML) analysis of high resolution vital parameter monitoring data surrounding the LISA procedure.Approach. Patients with a gestational age (GA) <32 weeks receiving LISA were included. Vital parameter data was obtained from a data warehouse. Physiological features (HR, RR, peripheral oxygen saturation (SpO2) and body temperature) were calculated in eight 0.5 h windows throughout a period 1.5 h before to 2.5 h after LISA. First, physiological data was analyzed to investigate differences between the CPAP-F and CPAP-Success (CPAP-S) groups. Next, the performance of two types of ML models (logistic regression: LR, support vector machine: SVM) for the prediction of CPAP-F were evaluated.Main results. Of 51 included patients, 18 (35%) had CPAP-F. Univariate analysis showed lower SpO2, temperature and heart rate variability (HRV) before and after the LISA procedure. The best performing ML model showed an area under the curve of 0.90 and 0.93 for LR and SVM respectively in the 0.5 h window directly after LISA, with GA, HRV, respiration rate and SpO2as most important features. Excluding GA decreased performance in both models.Significance. In this pilot study we were able to predict CPAP-F with a ML model of patient monitor signals, with best performance in the first 0.5 h after LISA. Using ML to predict CPAP-F based on vital signals gains insight in (possibly modifiable) factors that are associated with LISA failure and can help to guide personalized clinical decisions in early respiratory management.

Diagnostic-driven management of invasive fungal disease in hematology in the era of prophylaxis and resistance emergence: Dutch courage?

Patients receiving intensive anti-leukemic treatment or recipients of allogeneic hematopoietic stem cell transplantation (HSCT) are prone to develop invasive fungal disease caused by both Aspergillus and non-Aspergillus moulds. Overall mortality following invasive mould disease (IMD) is high; adequate and timely antifungal treatment seems to ameliorate the outcome, yet early diagnosis in the haematological patient remains a challenge for most clinicians. Prophylaxis and the empiric addition of antifungal therapy to neutropaenic patients with fever persisting or recurring during broad-spectrum antibiotic treatment is therefore standard of care in many institutions. However, aside from the potential for overtreatment and important side effects, the emergence of resistance to medical triazoles in Aspergillus fumigatus poses a risk for inadequate initial treatment. Initial voriconazole therapy in patients with azole-resistant invasive aspergillosis was recently shown to be associated with a 23% increased mortality rate compared to the patients with azole-susceptible infection, despite changing to appropriate antifungal therapy once resistance was detected. Moreover, fever is not always present with IMD; therefore, cases may be missed when relying solely on this symptom for starting diagnostic procedures and antifungal treatment. At our institution, a diagnostic-driven treatment approach for IMD was implemented relying on clinical but also laboratory markers to start antifungal treatment. We describe the basis and clinical implementation of our diagnostic-driven approach in this review.

Assessment of LV ejection fraction using real-time 3D echocardiography in daily practice: direct comparison of the volumetric and speckle tracking methodologies to CMR.

AIMS: This study is the first to directly compare two widely used real-time 3D echocardiography (RT3DE) methods of cardiac magnetic resonance imaging (CMR) and assess their reproducibility in experienced and less experienced observers. METHODS: Consecutive patients planned for CMR underwent RT3DE within 8 h of CMR with Philips (volumetric method) and Toshiba Artida (speckle tracking method). Left ventricular ejection fraction (LVEF), left ventricular end-diastolic volume (LVEDV) and end-systolic volume (LVESV) were measured using RT3DE, by four trained observers, and compared with CMR values. RESULTS: Thirty-five patients were included (49.7 ± 15.7 years; 55 % male), 30 (85.7 %) volumetric and 27 (77.1 %) speckle tracking datasets could be analysed. CMR derived LVEDV, LVESV and LVEF were 198 ± 58 ml, 106 ± 53 ml and 49 ± 15 %, respectively. LVEF derived from speckle tracking was accurate and reproducible in all observers (all intra-class correlation coefficients (ICC) > 0.86). LVEF derived from the volumetric method correlated well to CMR in experienced observers (ICC 0.85 and 0.86) but only moderately in less experienced observers (ICC 0.58 and 0.77) and was less reproducible in these observers (ICC = 0.55). Volumes were significantly underestimated compared with CMR (p < 0.001). CONCLUSION: This study demonstrates that both RT3DE methodologies are sufficiently accurate and reproducible for use in daily practice. However, experience importantly influences the accuracy and reproducibility of the volumetric method, which should be considered when introducing this technique into clinical practice.

Enhanced seasonal exchange of CO2 by northern ecosystems since 1960.

Seasonal variations of atmospheric carbon dioxide (CO2) in the Northern Hemisphere have increased since the 1950s, but sparse observations have prevented a clear assessment of the patterns of long-term change and the underlying mechanisms. We compare recent aircraft-based observations of CO2 above the North Pacific and Arctic Oceans to earlier data from 1958 to 1961 and find that the seasonal amplitude at altitudes of 3 to 6 km increased by 50% for 45° to 90°N but by less than 25% for 10° to 45°N. An increase of 30 to 60% in the seasonal exchange of CO2 by northern extratropical land ecosystems, focused on boreal forests, is implicated, substantially more than simulated by current land ecosystem models. The observations appear to signal large ecological changes in northern forests and a major shift in the global carbon cycle.

Review paper: Gene expression profiling in veterinary and human medicine: overview of applications and proposed quality control practices.

High throughput molecular analysis of veterinary tissue samples is being applied to a wide range of research questions aimed at improving survival, development of diagnostic assays, and improving the economics of commercial production of animal products. Many of these efforts also, implicitly or explicitly, have ramifications for the clinical care of humans and, potentially, animals. Here we provide an overview of applications of gene expression profiling in veterinary research and practice. We then focus on the current state of quality control and quality assurance efforts in gene expression profiling studies, underscoring lessons learned from such analysis of human samples. Finally, we propose practices aimed at ensuring the reliability and reproducibility of such assays. The implementation of quality assurance practices by a trained pathologist is an essential link in the chain of events leading ultimately to reliable and reproducible research findings and appropriate clinical care.

The long-term outcome of antenatal hydronephrosis up to 15 millimetres justifies a noninvasive postnatal follow-up.

AIM: To assess the incidence of urinary tract infections (UTIs) and surgery in infants with different grades of antenatal hydronephrosis (ANH) and to evaluate incidence, severity and course of underlying vesicoureteral reflux (VUR). METHODS: Retrospective data of 125 infants with ANH were collected. The patients were divided into two groups according to the anterior-posterior pelvis diameter: group I, 5-14 mm and group II, > or =15 mm. RESULTS: UTIs developed in 4 of 106 infants from group I and 5 of 19 infants from group II. Surgical interventions were performed on 1 of 106 patients of group I and 7 of 19 patients of group II. These differences were statistically significant (p-values 0.004 and <0.001, respectively). In group I, 6 of 106 patients had VUR; none of them required surgical intervention and only two developed a UTI (one of whom also had contralateral ureteropelvic junction obstruction). Five of 19 infants in group II had underlying VUR, four of them with associated anomalies, 1 infant required surgical correction and 4 developed UTIs. CONCLUSION: Infants with ANH up to 15 mm have a low incidence of UTIs and surgery and a low incidence and benign course of underlying VUR. Therefore, noninvasive postnatal follow-up is justified and standard voiding cystourethrography should not be performed, but only in cases of ureteric dilatation.

Differential expression of c-Met, its ligand HGF/SF and HER2/neu in DCIS and adjacent normal breast tissue.

AIMS: Tyrosine kinase receptors Her2/neu and c-Met play an important role in breast cancer development and progression. Our aim was to determine the expression of c-Met, its ligand hepatocyte growth factor/scatter factor (HGF/SF) and Her2/neu in ductal carcinoma in situ (DCIS) lesions of the breast (n = 39) by two different immunocytochemical techniques, classical immunohistochemistry and immunofluorescence, and to correlate their expression levels with histopathological and clinical characteristics. METHODS AND RESULTS: Both methods revealed similar c-Met staining patterns in both the in situ component and the adjacent normal tissue (P < 0.001). However, an imbalance in c-Met expression between tumour and surrounding normal tissue was correlated with high-grade DCIS (Van Nuys Grade 3). No correlation existed between Her2/neu and c-Met expression. High HGF/SF immunoreactivity was observed in 43.6% of the cases, yet the adjacent cellular stroma revealed only low levels of HGF/SF. No correlation existed between c-Met, Her2/neu or HGF/SF expression and clinicopathological factors. CONCLUSION: An imbalance in c-Met expression between tumour and surrounding normal tissue is associated with an aggressive DCIS phenotype. Moreover, c-Met and HGF/SF may contribute to tumour development by different means than those controlled by Her2/neu.

[Diagnostic image (321). A girl with 'bruises' on her abdomen]. / Diagnose in beeld (321). Een meisje met 'blauwe' plekken op de buik. Erythema ab igne.

A 12-year-old girl presented with a reticular skin abnormality on her abdomen, which was caused by the frequent use of hot water bottles to relieve her chronic stomachache. This skin condition is called erythema ab igne.

Identification of deregulated oncogenic pathways in renal cell carcinoma: an integrated oncogenomic approach based on gene expression profiling.

In this age of targeted therapy, identification of molecular pathways that are deregulated in cancer will not only elucidate underlying tumorigenic mechanisms, but may also help to determine the classes of drugs that are used for treatment. In kidney cancer, a spectrum of histological subtypes exists that are characterized both by distinct molecular signatures and increasingly by distinct molecular pathways that are deregulated in each subtype. For example, the VHL/hypoxia pathway is well-known to be deregulated in clear cell renal cell carcinoma (RCC) whereas in papillary RCC activation of the HGF/Met pathway has been implicated. Additional molecular pathways, many not yet identified, may also be involved in the development of the different histologic subtypes. Moreover, differences in pathway activation may reflect differences in tumor progression and response to treatment. In this article, we describe an oncogenomic approach, based on integrative analysis of gene expression profiling data. In this approach, gene expression data is used to identify both cytogenetic abnormalities and molecular pathways that are deregulated in RCC. Ideally, predicted pathway abnormalities can be linked to predicted cytogenetic abnormalities to identify likely candidate genes. Although further cellular and functional studies are warranted to validate the computational models, development of such models in RCC have the potential to open up new avenues of molecular research and may have significant diagnostic and therapeutic implications.

Neutralizing monoclonal antibodies to hepatocyte growth factor/scatter factor (HGF/SF) display antitumor activity in animal models.

The hepatocyte growth factor (HGF/SF) receptor, Met, regulates mitogenesis, motility, and morphogenesis in a cell type-dependent fashion. Activation of Met via autocrine, paracrine, or mutational mechanisms can lead to tumorigenesis and metastasis and numerous studies have linked inappropriate expression of this ligand-receptor pair to most types of human solid tumors. To prepare mAbs to human HGF/SF, mice were immunized with native and denatured preparations of the ligand. Recloned mAbs were tested in vitro for blocking activity against scattering and branching morphogenesis. Our results show that no single mAb was capable of neutralizing the in vitro activity of HGF/SF, and that the ligand possesses a minimum of three epitopes that must be blocked to prevent Met tyrosine kinase activation. In vivo, the neutralizing mAb combination inhibited s.c. growth in athymic nu/nu mice of tumors dependent on an autocrine Met-HGF/SF loop. Importantly, growth of human glioblastoma multiforme xenografts expressing Met and HGF/SF were markedly reduced in the presence of HGF/SF-neutralizing mAbs. These results suggest interrupting autocrine and/or paracrine Met-HGF/SF signaling in tumors dependent on this pathway is a possible intervention strategy.

A candidate prostate cancer susceptibility gene at chromosome 17p.

It is difficult to identify genes that predispose to prostate cancer due to late age at diagnosis, presence of phenocopies within high-risk pedigrees and genetic complexity. A genome-wide scan of large, high-risk pedigrees from Utah has provided evidence for linkage to a locus on chromosome 17p. We carried out positional cloning and mutation screening within the refined interval, identifying a gene, ELAC2, harboring mutations (including a frameshift and a nonconservative missense change) that segregate with prostate cancer in two pedigrees. In addition, two common missense variants in the gene are associated with the occurrence of prostate cancer. ELAC2 is a member of an uncharacterized gene family predicted to encode a metal-dependent hydrolase domain that is conserved among eukaryotes, archaebacteria and eubacteria. The gene product bears amino acid sequence similarity to two better understood protein families, namely the PSO2 (SNM1) DNA interstrand crosslink repair proteins and the 73-kD subunit of mRNA 3' end cleavage and polyadenylation specificity factor (CPSF73).

Predictors of vaccination rates during a mass meningococcal vaccination program on a college campus.

Factors contributing to students' compliance with mass vaccination programs during meningococcal outbreaks have not been well described. A 1997 mass vaccination campaign at Michigan State University provided an opportunity to study such factors. Of 34,024 students in the target population, 17,538 (51.5%) were vaccinated in 5 days. Vaccination rates were higher for women (47.9%) than for men (43.1%) and higher for on-campus residents (65.3%) than for off-campus residents (35.6%). For each year of students' age beyond 19, the adjusted odds of vaccination were reduced by 0.82. Adjusted odds ratios for vaccination, with White students as the reference group at 1.0, were 1.33 for Asian American students, 0.97 (not significant) for Hispanic students, 0.82 for African American students, and 0.80 for Native American students. Students from the Colleges of Business, Engineering, Communication, and Natural Science had the highest vaccination rates; those from the College of Arts and Letters had the lowest rates.

Evidence of linkage of familial hypoalphalipoproteinemia to a novel locus on chromosome 11q23.

Coronary heart disease (CHD) accounts for half of the 1 million deaths annually ascribed to cardiovascular disease and for almost all of the 1.5 million acute myocardial infarctions. Within families affected by early and apparently heritable CHD, dyslipidemias have a much higher prevalence than in the general population; 20%-30% of early familial CHD has been ascribed to primary hypoalphalipoproteinemia (low HDL-C). This study assesses the evidence for linkage of low HDL-C to chromosomal region 11q23 in 105 large Utah pedigrees ascertained with closely related clusters of early CHD and expanded on the basis of dyslipidemia. Linkage analysis was performed by use of 22 STRP markers in a 55-cM region of chromosome 11. Two-point analysis based on a general, dominant-phenotype model yielded LODs of 2.9 for full pedigrees and 3.5 for 167 four-generation split pedigrees. To define a localization region, model optimization was performed using the heterogeneity, multipoint LOD score (mpHLOD). This linkage defines a region on 11q23.3 that is approximately 10 cM distal to-and apparently distinct from-the ApoAI/CIII/AIV gene cluster and thus represents a putative novel localization for the low HDL-C phenotype.

Prostate cancer susceptibility locus HPC1 in Utah high-risk pedigrees.

A prostate cancer susceptibility locus ( HPC1 ) at 1q24-25 has been identified. Subsequent analysis showed that the majority of the evidence for localization was provided by families with relatively young (<65 years) average age at diagnosis. We examined evidence for linkage to this region in a set of 41 extended multi-case prostate cancer pedigrees containing 440 prostate cancer cases. Genotyping of five short tandem repeat markers in the region was performed on DNA from 1724 individuals, including 284 prostate cancer cases. In comparison with the families reported in the initial localization, the Utah pedigrees are generally much larger (average of 10.7 versus 5.1 cases) and have an older average age at diagnosis (69 versus 65 years). Two- and three-point linkage analyses were conducted using a previously reported model and provided replication for HPC1 (two-point: LOD = 1.73, P = 0.005 at D1S196; three-point: LOD = 2.06, P = 0.002 for the interval D1S196-D1S416 ). The youngest quartile (by median age at diagnosis) yielded a maximum LOD of 2.82, P = 0. 0003 (at D1S215-D1S222 ), compared with a maximum LOD of 0.73, P = 0. 07 for the oldest quartile pedigrees at the same locus. Further analysis with an age-dependent model, specifying higher sporadic rates for older cases, suggests that the linkage evidence may be lower than expected given the power of the resource due to a high sporadic rate in the large Utah pedigrees.

Respiratory ammonia output and blood ammonia concentration during incremental exercise.

The aim of this study was to investigate whether the increase of ammonia concentration and lactate concentration in blood was accompanied by an increased expiration of ammonia during graded exercise. Eleven healthy subjects performed an incremental cycle ergometer test. Blood ammonia, blood lactate and the amount of expired ammonia were measured until 30 minutes post exercise. The expired air was guided through a flow chamber filled with a sulphuric acid solution to trap the expired ammonia. Blood ammonia, blood lactate increased more than proportionally and the amount of expired ammonia (in micromol/min) increased exponentially with the workload. Post-exercise the amount of expired ammonia decreased within a few minutes back to pre-exercise levels while the concentrations of lactate and ammonia in blood decreased much more slowly and were still elevated after 30 minutes of recovery. We conclude that the more than proportional increase of ammonia and lactate during graded exercise, is accompanied with an exponential increase of expired ammonia output. Faster and more accurate ammonia gas detection techniques are necessary to quantify more precisely the respiratory ammonia output during graded exercise.

Water vapour and carbon dioxide decrease nitric oxide readings.

Measurement of nitric oxide levels in exhaled air is commonly performed using a chemiluminescence detector. However, water vapour and carbon dioxide affect the chemiluminescence process. The influence of these gases at the concentrations present in exhaled air, has not yet been studied. For this in vitro study, mixtures of 50, 100 and 200 parts per billion (ppb) NO in air were prepared and fed into the NO analyser either directly or bubbled through water. Mixtures with CO2 were prepared by adding 0-10% CO2 to the diluent air. We found a significant decrease in NO readings in the water-saturated samples compared to the dry gas (p < 0.001), strongly dependent on the partial pressure of water. NO levels in exhaled air (mean 10 +/- 2 ppb) showed a decrease of 17 +/- 3% when water vapour was not absorbed. From the experiments with CO2 we found a decrease in NO reading of 1.04 +/- 0.07% per volume CO2 (%). Presence of water vapour, thus, leads to a systematic underestimation of NO levels. Insertion of a water absorber might, therefore, be advantageous. The influence of CO2 concentrations in the normal respiratory range is negligible. With high expiratory CO2 levels as applied in permissive hypercapnia, the effects may be substantial.

Mini-Wright peak flow meters are reliable after 5 years use. Dutch CNSLD Study Group.

In studies with a long-term follow-up, peak expiratory flow (PEF) meters are often used to assess bronchial obstruction. The question arises whether data obtained with these frequently used meters are still reliable after several years of use, and whether the old meters should be renewed after a certain period. In the present study, we tested the reliability of PEF values measured with mini-Wright PEF meters that had been used frequently for 5 yrs. The values obtained with these meters were compared with values measured with identical but new meters, in 50 patients with obstructive airways disease. Though statistically significant, there was no clinically significant difference in mean PEF measured with the old and new meters in most patients (mean difference 10.2 L.min-1). However, on an individual basis, the differences between old and new meters could be large (upper and lower limits of agreement (mean +/- 2 SD) being 63.6 and -43.2 L.min-1, respectively). We conclude that mean peak expiratory flow values measured with frequently used mini-Wright peak expiratory flow meters are still reliable after 5 yrs. In long-term studies, renewal of peak expiratory flow meters should be restricted to cases of obvious malfunction.

Multilocus quantitative trait analysis using the multipoint identity-by-descent method.

The multipoint identity-by-descent method (MIM) was extended to test for evidence of quantitative trait loci in two independent genetic regions. This method is a fast and feasible implementation of a multiple-marker, two-region linkage analysis for quantitative traits. It tests for significant evidence of quantitative trait loci (QTL) in neither, one or both genetic regions tested, and could be extended to an arbitrary number of independent genetic regions. A two-stage analysis was used for the nuclear family data from GAW10. Initially, an analysis of the genomic search was carried out using single-region MIM, with sets of six adjacent markers. Chromosomal regions that showed some evidence of linkage were identified and used in a two-region MIM analysis.